Pharmaceutical compositions containing anti-beta 1 integrin compounds and uses

Abstract

Organic Anti-Beta 1 integrin compounds useful for inhibiting cell-adhesion.

1 . A method for inhibiting activity of a plurality of integrins containing a φ1 subunit, the method comprising administering to a system containing said integrins, an effective amount of a pan-β1 integrin antagonist compound of Formula 1: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein: 
 R 1  is 
 1) C1-10 alkyl,  
 2) C2-10alkenyl,  
 3) C2-10 alkynyl,  
 4) Cy,  
 5) Cy—C1-10 alkyl,  
 6) Cy—C2-10 alkenyl,  
 7) Cy—C2-C10 alkynyl,  
 wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from R a ; and Cy is optionally substituted with one to four substituents independently selected from R b ;  
 
 R 2  is 
 1) hydrogen,  
 2) C1-10 alkyl,  
 3) C2-10 alkenyl,  
 4) C2-10 alkynyl,  
 5) aryl,  
 6) aryl-C1-10 alkyl,  
 7) heteroaryl,  
 8) heteroaryl-C1-10 alkyl,  
 wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from R a  and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from R b ;  
 
 R 3  is 
 1) hydrogen,  
 2) C1-10 alkyl,  
 3) Cy, or  
 4) Cy—C1-10 alkyl,  
 wherein alkyl is optionally substituted with one to four substituents independently selected from R a ; and Cy is optionally substituted with one to four substituents independently selected from R b ;  
 
 R 4  is 
 1) hydrogen,  
 2) C1-10 alkyl,  
 3) C2-10 alkenyl,  
 4) C2-10 alkynyl,  
 5) Cy,  
 6) Cy—C1-10 alkyl,  
 7) Cy—C2-10 alkenyl,  
 8) Cy—C2-10 alkynyl,  
 wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from phenyl and R x , and Cy is optionally substituted with one to four substituents independently selected from R y ; or  
 
 R 3 , R 4  or R 3 , R 5  and the atoms to which they are attached together form a mono- or bicyclic ring containing 0-2 additional heteroatoms selected from N, O, and S;  
 R 5  is 
 1) hydrogen,  
 2) C1-10 alkyl,  
 3) C2-10 alkenyl,  
 4) C2-10 alkynyl,  
 5) aryl,  
 6) aryl-C1-10 alkyl,  
 7) heteroaryl,  
 8) heteroaryl-C1-10 alkyl,  
 wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from R x  and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from R y ; or  
 
 R 4 , R 5  and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N, O and S;  
 R 6 , R 7 , and R 8  are each independently selected from the group consisting of 
 1) a group selected from R d , and  
 2) a group selected from R x ; or  
 two of R 6 , R 7 , and R 8  and the atom to which both are attached, or two of R 6 , R 7 , and R 8  and the two adjacent atoms to which they are attached, together form a 5-7 membered saturated or unsaturated monocyclic ring containing zero to three heteroatoms selected from N, O or S,  
 
 R 12  is 
 1) hydrogen,  
 2) C1-10 alkyl,  
 3) C2-10 alkenyl,  
 4) C2-10 alkynyl,  
 5) Cy,  
 6) Cy—C1-10 alkyl,  
 7) Cy—C2-10 alkenyl,  
 8) Cy—C2-10 alkynyl,  
 wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from phenyl and R x , and Cy is optionally substituted with one to four substituents independently selected from R y ;  
 
 R 13  is 
 1) hydrogen,  
 2) C1-10 alkyl,  
 3) C2-10 alkenyl,  
 4) C2-10 alkynyl,  
 5) aryl,  
 6) aryl-C1-10 alkyl,  
 7) heteroaryl,  
 8) heteroaryl-C1-10 alkyl,  
 wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from R x  and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from R y ;  
 
 R a  is 
 1) Cy, or  
 2) a group selected from R x ;  
 wherein Cy is optionally subsituted with one to four substituents independently selected from R c ;  
 
 R b  is 
 1) a group selected from R a ,  
 2) C1-10 alkyl,  
 3) C2-10 alkenyl,  
 4) C2-10 alkynyl,  
 5) aryl C1-10 alkyl,  
 6) heteroaryl C1-10 alkyl,  
 wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from R c ;  
 
 R c  is 
 1) halogen,  
 2) NO 2 ,  
 3) C(O)OR f    
 4) C1-4 alkyl,  
 5) C1-4 alkoxy,  
 6) aryl,  
 7) aryl C1-4 alkyl,  
 8) aryloxy,  
 9) heteroaryl,  
 10) NR f R g ,  
 11) NR f C(O)R g ,  
 12 NR f C(O)NR f R g ,  
 13) CN;  
 14) C(O)Cy; or  
 15) C(O)alkyl.  
 
 R d  and R e  are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy and Cy C1-10 alkyl, aryl, heteroaryl, aryl-substituted aryl, aryl substituted heteroaryl, heteroaryl-substituted heteroaryl  
 wherein alkyl, alkenyl, alkynyl, heteroaryl and Cy is optionally substituted with one to four substituents independently selected from R c ;  
 R d  and R e  together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen,  
 R f  and R g  are independently selected from hydrogen, C1-10 alkyl, Cy and Cy—C1-10 alkyl wherein Cy is optionally substituted with C1-10 alkyl; or R f  and R g  together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein the nitrogen is optionally substituted with C(O)R e , SO 2 R e ; or SO 2 NR d R e ;  
 R h  is 
 1) hydrogen,  
 2) C1-10 alkyl,  
 3) C2-10 alkenyl,  
 4) C2-10 alkynyl,  
 5) cyano,  
 6) aryl,  
 7) aryl C1-10 alkyl,  
 8) heteroaryl,  
 9) heteroaryl C1-10 alkyl, or  
 10) —SO2R i ;  
 wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from R a ; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R b ;  
 
 R i  is 
 1) C1-10 alkyl,  
 2) C2-10 alkenyl,  
 3) C2-10 alkynyl, or  
 4) aryl;  
 wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R c ;  
 
 R j  is selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy and Cy C1-10 alkyl, aryl, heteroaryl, aryl-substituted aryl, aryl substituted heteroaryl, heteroaryl-substituted heteroaryl  
 wherein alkyl, alkenyl, alkynyl, heteroaryl, and Cy is optionally substituted with one to four substituents independently selected from R c    
 R x  is 
 1) —OR d ,  
 2) —NO 2 ,  
 3) halogen,  
 4) —S(O) m R d    
 5) —SR d ,  
 6) —S(O) 2 OR d ,  
 7) —S(O) m NR d R e ,  
 8) —NR d R e ,  
 9) —O(CR f R g ) n NR d R e ,  
 10) —C(O)R d ,  
 11) —CO 2 R d ,  
 12) —CO 2 (CR f R g ) n CONR d R e ,  
 13) —OC(O)R d ,  
 14) —CN,  
 15) —C(O)NR d R e ,  
 16) —NR d C(O)R e ,  
 17) —OC(O)NR d R e ,  
 18) —NR d C(O)OR e ,  
 19) —NR d C(O)NR d R e ,  
 20) —CR d (N—OR e ),  
 21) —CF 3 ,  
 22) oxo,  
 23) NR d C(O)NR d SO 2 R i ,  
 24) NR d S(O) m R e ,  
 25) —OS(O) 2 OR d ,  
 26) —OP(O)(OR d ) 2 ; or  
                     
 
 R y  is 
 1) a group selected from R x ,  
 2) C1-10 alkyl,  
 3) C2-10 alkenyl,  
 4) C2-10 alkynyl,  
 5) aryl C1-10 alkyl,  
 6) heteroaryl C1-10 alkyl,  
 7) cycloalkyl,  
 8) heterocyclyl;  
 9) aryl;  
 10) heteroaryl  
 wherein alkyl, alkenyl, alkynyl, heteroaryl and aryl are each optionally substituted with one to four substituents independently selected from R x ;  
 
 Cy is 
 cycloalkyl, heterocyclyl, aryl, or heteroaryl;  
 
 m is an integer from 1 to 2;  
 n is an integer from 1 to 10;  
 X is 
 1) —C(O)OR d    
 2) -5-tetrazolyl;  
 3) —(CR f R g )COOR d    
 
 Y is 
 1) —S(O) 2 —; or  
 2) —S(O) 2 NR e    
 
 Z and A are independently selected from —C— and —C—C—;  
 B is selected from the group consisting of 
 1) a bond,  
 2) —C—,  
 3) —C—C—;  
 4) —C═C—,  
 5) a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur; and  
 
 5) —S(O) m —.  
 
     
     
         2 . A method of  claim 1 , which comprises administering an effective amount of a compound of Formula 2: 
       
         
           
           
               
               
           
         
         Wherein Ar is aryl, heteroaryl, aryl-substituted aryl, aryl substituted heteroaryl, heteroaryl-substituted heteroaryl  
         and R z  is: 
 a) —OR d    
 b) —NH 2    
 c) NHR d    
 d) —NR d C(O)R e    
 e) —NR d S(O) m R e ; and  
 
         wherein R d  and R e  are as recited in  claim 1  and R 9  is selected from H and R y .  
       
     
     
         3 . A method of  claim 2 , which comprises administering an effective amount of a compound of Formula 3: 
       
         
           
           
               
               
           
         
       
       wherein Rz is as recited in  claim 2  and R 9  is selected from H and R y .  
     
     
         4 . A method for inhibiting a plurality of integrins containing a β1 subunit, wherein the method comprises administering to a system containing said integrins an effective amount of a compound of  claim 2  or a pharmaceutically acceptable salt thereof, wherein Ar is aryl, heteroaryl, aryl-substituted aryl, aryl substituted heteroaryl, heteroaryl-substituted heteroaryl 
 and R z  is: 
 a) —OR d    
 b) —NH 2    
 c) NHR d    
 d) —NR d C(O)R e    
 e) —NR d S(O) m R e ; wherein R d  and R e  are as recited in  claim 1  and and R 9  is selected from H and R y .  
 
 
     
     
         5 . A method for inhibiting a plurality of integrins containing a β1 subunit, the method comprisings administering to a system containing said integrins an effective amount of a compound of  claim 3  or a pharmaceutically acceptable salt thereof, wherein R z  is as recited in  claim 2 .  
     
     
         6 . A method of  claim 3 , which comprises administering an effective amount of a compound of Formula 4: 
       
         
           
           
               
               
           
         
       
       wherein Ar is aryl, heteroaryl, aryl-substituted aryl, aryl substituted heteroaryl which are optionally substituted with one to four substituents independently selected from R x  and R 9  is selected from H and R y .  
     
     
         7 . A method of  claim 1 , which comprises administering an effective amount of a compound of Formula 5: 
       
         
           
           
               
               
           
         
       
       R 9  is selected from H and R y .  
     
     
         8 . A method of  claim 7 , which comprises administering an effective amount of a compound of Formula 6: 
       
         
           
           
               
               
           
         
       
       where Ar is aryl, heteroaryl, aryl-substituted aryl, aryl substituted heteroaryl which are optionally substituted with one to four substituents independently selected from R x  and R 9  is selected from H and R y .  
     
     
         9 . A composition having the formula 
       D-L-P wherein: 
       D is a small organic molecule, said organic molecule attached to linker L, wherein linker L is not significantly cleavable using human enzymes, and wherein P is a biocompatible polymer.  
     
     
         10 . The composition of  claim 9  wherein, 
 D is a pan-beta1 integrin antagonist of Formula 1 having at least one bond selected from the group consisting of an amide, amine, ether, urea, thiourea, sulfonyl urea, sulfonyl amide, thio ether and carbon-carbon bond, and  
 L is  
                     
 wherein R 10  and R 11  are independently selected from the group consisting of H, C 1-6  alkyls, aryls, substituted aryls, aralkyls, heteroalkyls, substituted heteroalkyls and substituted C 1-6  alkyls, q a positive integer and F is selected from O, NR 1 , S, SO, SO 2 , and wherein P is a polyalkylene oxide.  
 
     
     
         11 . A method of inhibiting the activity of a plurality of β1-subunit containing integrins, comprising administering to a system containing said plurality, a pan-β1 antagonist selected from the group consisting of the small molecules of Table 1.